Evaluation of Second-Line Treatment for Castration-Resistant Prostate Cancer following the Administration of Upfront Androgen Receptor Signaling Inhibitors

This study evaluated the effects of docetaxel and androgen receptor signaling inhibitors as second-line treatments in patients with castration-resistant prostate cancer after androgen receptor signaling inhibitors as first-line treatment. This study retrospectively evaluated the clinical outcomes of second-line treatment with docetaxel or androgen receptor signaling inhibitor in patients with castration-resistant prostate cancer who received first-line treatment with androgen receptor signaling inhibitors. Clinical backgrounds and outcomes were compared between docetaxel and androgen receptor signaling inhibitors as second-line treatment. Of 59 patients, 21 (35.6%) and 38 (64.4%) received docetaxel and androgen receptor signaling inhibitors as second-line treatment after first-line treatment with androgen receptor signaling inhibitors, respectively. In the second-line setting, the median progression-free survival was longer with androgen receptor signaling inhibitor than with docetaxel (17 versus 6 months, P=0.014). In the first-line setting, the median progression-free survival was longer with androgen receptor signaling inhibitors than with docetaxel (32 versus 25 months, P=0.014); however, no significant difference was found in the overall survival. Multivariate analysis revealed that there was no significant association between second-line treatment and survival, and first-line treatment with abiraterone was identified as a prognostic factor for progression-free survival. Subgroup analysis showed that the abiraterone–enzalutamide sequence was more effective than the other three sequences for progression-free survival and overall survival. This study suggests that second-line treatment with an androgen receptor signaling inhibitor for castration-resistant prostate cancer after androgen receptor signaling inhibitors as first-line treatment may be more beneficial, particularly with abiraterone as the upfront treatment.


Introduction
Prostate cancer (PC) is the second most common malignant tumor in men worldwide, and in 2020, the incidence of PC in men exceeded that of lung cancer in Japan [1].Androgen deprivation therapy (ADT) is the standard treatment modality for advanced PC.However, most PCs develop resistance to initial hormonal therapy after several years of ADT and often progress to castration-resistant prostate cancer (CRPC) [2].Docetaxel (DTX) was used from 2004 to improve the prognosis of CRPC patients [3], and it has become the standard treatment for CRPC.Recently, efective systemic agents for CRPC have increased, including androgen receptor signaling inhibitors (ARSIs) such as abiraterone (ABI) and enzalutamide (ENZA).ABI and ENZA as secondline agents following DTX therapy and as frst-line agents before DTX therapy were found to improve survival compared with placebo in metastatic CRPC (mCRPC) [4][5][6][7].Tese agents are thought to be less toxic than DTX [8].Terefore, since ABI and ENZA were approved for CRPC by the Pharmaceuticals and Medical Devices Agency in Japan in 2014, they have been widely used as standard frst-line therapies for CRPC in Japan [9].However, no reliable guidelines have been established to select the optimal second-line treatment agent for CRPC patients that progressed after frst-line treatment with ARSIs.Few retrospective reports have directly compared the efcacy of ARSIs and DTX as the second-line treatment for CRPC [10,11].However, the optimal therapeutic sequence of these several available modalities in frst-and second-line treatment for CRPC is still debated.Furthermore, there may be a common antitumor mechanism and cross-resistance among ABI, ENZA, and DTX with each other [12][13][14].
Terefore, the purpose of this study was to evaluate the efcacy of DTX compared with ARSI in the second-line treatment of CRPC patients who received ARSI as frst-line treatment.Furthermore, we evaluated whether patients who have disease progression during frst-line ARSI should be subsequently treated with another ARSI or DTX.

Study Population.
Tis study retrospectively analyzed patients with CRPC who received frst-line treatment with ABI or ENZA between 2012 and 2022.Patients who received ARSIs or DTX before ARSIs for hormone-sensitive PC were excluded.Patient characteristics, including age, prostate-specifc antigen (PSA) level, Gleason score, radiological data, and treatment modality for hormonesensitive PC, were obtained from the electronic medical records.Disease progression was defned as an increase in the PSA level of >25% or an absolute increase of ≥2 ng/mL above the nadir.CRPC was defned as the presence of PSA progression despite continuous treatment with luteinizing hormone-releasing hormone agonist/antagonist.Patients with no evidence of metastatic cancer at or before CRPC were considered to have non-mCRPC (nmCRPC), and patients with any evidence of metastatic cancer at or before CRPC were considered to have mCRPC.DTX was administered at the dose of 70 mg/m 2 every 3 weeks as a 1 h infusion.Patients received ABI 1000 mg orally once daily plus prednisone 5 mg orally twice daily.Tey received ENZA 160 mg orally once daily.Dose adjustments and treatment intervals were individualized based on the patient's condition and adverse events (AE), as determined by the physician.
Tis study was conducted with the approval of the Japanese Red Cross Wakayama Medical Center Institutional Review Board (approval no.1201) and in accordance with the Declaration of Helsinki.

Outcome Measures.
Progression-free survival (PFS) in second-line treatment was assessed by the time from the start of second-line treatment to disease progression.Combined PFS was calculated from the start of frst-line treatment with ARSIs to the time of disease progression on the second-line treatment.In addition, overall survival (OS) was defned as the time from the start of primary ARSI treatment to death from any cause, and PSA kinetics for each treatment line and drug were measured using the PSA value at the start of each line, nadir, and at each progression.
Treatment-related adverse events (AEs) were evaluated by the Common Terminology Criteria Adverse Events, version 5.

Statistical Analysis.
Continuous variables are reported as median and interquartile range.Te characteristics of the patients in the two treatment groups were compared by the Mann-Whitney U test for continuous variables and the chi-square test and Fisher's exact test for categorical variables.PFS and OS were estimated by the Kaplan-Meier method, and the log-rank test was used to compare survival in the categorized cohorts.Univariate and multivariate analyses were performed using univariate and multivariate Cox proportional hazards analyses.All statistical analyses were performed using JMP Pro 16 (SAS Institute Inc., Cary, NC, USA).P values of <0.05 were considered signifcant.

Clinical Characteristics.
A total of 59 patients were included.All patients received frst-line treatment with ABI or ENZA for CRPC.Of these patients, 21 received secondline chemotherapy with DTX, and 38 received second-line treatment with ARSIs.Patient characteristics are shown in Table 1.In patients with CRPC, the median PSA level in the ARSI-ARSI group was higher than that in the ARSI-DTX group (P � 0.033), and the number of patients who received frst-line treatment with ABI was higher in the ARSI-ARSI group than in the ARSI-DTX group.However, no diference in age, Gleason score, rate of metastatic disease, duration of frst-line treatment, or PSA level at the initiation of secondline treatment was found between the two groups.

Clinical Outcomes.
Te median PFS in the second-line treatment with ARSIs was 17 months, which was signifcantly longer than that with DTX (P � 0.014; Figure 2(a)).Te median combined PFS in the ARSI-ARSI group (32 months) was signifcantly longer than that in the ARSI-DTX group (25 months) (P � 0.024; Figure 2(b)).Furthermore, the median OS in the ARSI-ARSI group (62 months) was longer than that in the ARSI-DTX group (42 months).However, the diference in OS was not statistically signifcant (P � 0.073; Figure 2(c)).

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Prostate Cancer

Prostate Cancer
However, no signifcant diferences in OS were found in the multivariate analysis, and the second-line treatment did not correlate with OS.Although metastasis did not correlate with OS and PFS in the univariate analysis (Tables 2, 3, and 4), subgroup analyses were performed for PFS and OS in patients with mCRPC.In patients with mCRPC, the median PSA level at start of frst-line treatment in the ARSI-ARSI group was higher than that in the ARSI-DTX group (14.8 ng/ml vs. 4.8 ng/ml; P � 0.009).However, no diference in other factors was found between the two groups.Te median PFS of mCRPC in the second-line treatment with ARSIs was 17 months, which was signifcantly longer than that with DTX (P � 0.026; Figure 3(a)), but there were no signifcant diferences in OS and combined PFS (P � 0.402 and P � 0.161; Figures 3(b) and 3(c), respectively).Whereas in patients with nmCRPC, there were no signifcant diferences in OS, PFS, and combined PFS by treatment sequences due to smaller sample size.
AEs were observed in 4 (8.9%) of all 45 patients treated with ABI and included edema, hypertension, fatigue, and elevation of liver enzymes.Tree of these patients required a dose reduction for ABI due to AE. Whereas, AEs were observed in 8 (15.4%) of all 52 patients treated with ENZA, including fatigue (n � 4), nausea (n � 2) dysgeusia (n � 1), and hypertension (n � 1).Five of these patients required a dose reduction for ENZA due to AE.All of these AEs were grade 1 or 2, and no grade 3 or above AEs were observed.No patient required discontinuation of ABI or ENZA due to AE.In 21 patients treated with DTX, 16 patients (71.4%) had neutropenia, including two patients with grade 3 and 14 patients with grade 4.Although two of these 14 patients with grade 4 neutropenia required dose reduction for DTX, all patients were able to continue treatment with DTX by using granulocyte colony-stimulating factor.

Discussion
Although ARSIs, including ABI and ENZA, improve prognosis in patients with CRPC [4][5][6][7], the optimal ARSIs, and showed that ARSIs as the second-line treatment were associated with a longer PFS than DTX.However, this longer PFS did not afect OS, and there was no signifcant diference in the multivariate analysis.Te results also showed that the time to CRPC and the frst-line treatment with ABI were signifcant prognostic factors for PFS.
To the best of our knowledge, no prospective studies have compared DTX with ARSIs as the second-line treatment for CRPC.Some retrospective studies have reported the efcacy of DTX after ARSI treatment in mCRPC patients.Miyake et al. suggested that the PSA response, PFS, and OS in second-line treatment with DTX were signifcantly better than those with ARSIs in patients with mCRPC [15].Similarly, Matsubara et al. reported a signifcantly better PFS in patients with mCRPC who received DTX as second-line treatment than in those who received ARSIs [16].However, in this study, PFS and OS in CRPC patients who received ARSIs as the second-line treatment were better than those in patients who received DTX, and these results are not consistent with previous reports.Te discrepancies between the previous reports and our study may have several possible reasons.Our study included both patients with nmCRPC and mCRPC.However, these two studies included only patients with mCRPC.Furthermore, we had unequal numbers of patients with ABI or ENZ used as the frst-line treatment in each of the DTX and ARSI second-line treatment groups.Several reports have compared the efcacy of ABI and ENZ as the frst-line agents for CRPC, and these results varied and were unclear.A meta-analysis suggested that better survival was found with ENZA than with ABI in mCRPC patients [17].However, a network Prostate Cancer meta-analysis did not fnd a diference in the survival between ABI and ENZA for mCRPC [18].In addition, a network meta-analysis of ARSIs for nmCRPC indicated that ABI provided a comparable survival beneft with other ARSI [19].
Two retrospective reports have compared ARSIs and DTX as second-line treatments for nmCRPC or mCRPC after frst-line treatment with ARSI [10,11].Tese reports suggested that DTX as second-line treatment is more benefcial than ARSIs in patients who have received ARSIs as frst-line treatment.Tese results also difer from those of our study.In these two reports, progression was evaluated based on not only PSA but also clinical and radiological fndings.However, in our study, progression was assessed using PSA alone.Tese diferences may afect the interpretation of the results.Te Advanced Prostate Cancer Consensus Conference 2015 recommended that progression should not be assessed on only increasing PSA and that the presence of at least 2 of the 3 criteria, including symptomatic progression, PSA progression, and radiographic progression, should be considered progression [20].Many patients receiving ARSI therapy are evaluated using PSA alone, additional imaging studies for PSA progression are performed in daily clinical practice.Matsumoto et al. reported that the median time to CRPC was shorter (DTX 16.1 months and ARSI 19.8 months) and the median PSA levels at both frst-line (DTX 14.2 ng/mL and ARSI 16.0 ng/ mL) and second-line (DTX 39.0 ng/mL and ARSI 24.9 ng/ mL) treatments were higher than those in our study [10].Terefore, more aggressive cancers may be included in the study.Broyelle et al. reported that the median age at frst-line treatment was 66.3 years [11], which was younger than our cohort, and more patients received DTX as the second-line treatment (DTX, n = 71; ARSI, n = 37).Tese fndings from previous reports and our study suggest that DTX as secondline treatment after progression in frst-line treatment with ARSI may be potentially benefcial compared to second-line treatment with ARSI in younger CRPC patients or patients with more aggressive CRPC and that second-line treatment with ARSI may be more appropriate for patients in whom DTX cannot be administered or in those with less aggressive CRPC.However, although the PSA level at start of frst-line treatment was higher in the ARSI-ARSI group than in the ARSI-DTX group, the PFS in second-line treatment with DTX was signifcantly shorter in patients with mCRPC in the subgroup analysis of our study.Generally, younger patients with more aggressive CRPC, such as multiple bone and visceral metastases, are commonly treated with DTX as the frst-line treatment, and older patients with less aggressive CRPC or lower performance status are likely to receive ARSI as frst-line treatment [21].Tese fndings from previous report and our study suggest that DTX in earlier phase may be appropriate for more aggressive CRPC.Tus, in a real-world setting, patient characteristics may infuence the selection of treatment for CRPC.
In this study, although no signifcant association was found between survival and PSA response or duration of frst-line treatment, the PFS in second-line treatment and combined PFS were signifcantly shorter in patients with ENZA as frst-line treatment.Tese fndings suggest that ARSIs at progression may be benefcial when ABI is used frst.Although the ABI-ENZA sequence was more efective than the other three sequences in terms of combined PFS and OS in the subgroup analysis, there were no signifcant  Prostate Cancer diferences between the ABI-DTX sequence and the ENZA-ABI or ENZA-DTX sequences.Mezynski et al. reported that the DTX activity in patients with mCRPC progression after frst-line treatment with ABI appears lower [14].Tese results and our data suggest that there may be cross-resistance between ABI and DTX.Furthermore, several studies have reported that there may be cross-resistance between ABI and ENZA [12,13].ENZA retains its clinical activity as a second-line treatment after ABI, whereas ABI does not retain its second-line activity after ENZA.Our fndings are also consistent with these reports.Because these reports were retrospective or had a small sample size, their results are inconclusive regarding the optimal order of treatment.In addition, no studies have reported crossresistance between ENZA and DTX.Terefore, larger prospective studies are needed to establish the optimal treatment sequence considering cross-resistance.Tis study has some limitations.First, this study has a retrospective design with a small sample size.Terefore, the diferent numbers of patients in the ARSI and DTX groups may lead to heterogeneity in baseline characteristics and measurements.In particular, the subgroup analysis of the four groups with diferent sequences may have been underpowered to detect true diferences.Second, this study did not consider subsequent lines of treatment.For example, the ABI-ENZA group may have improved prognosis because of subsequent treatment including DTX, cabazitaxel, and Radium-223.Furthermore, no strictly regulated criteria are available for the selection of second-line agents and the timing of starting second-line treatment because of the retrospective setting.Tus, some factors, including the time of data collection, timing of starting second-line treatment, and selection of second-line agents, could be biased because of the dependence on individual physicians.Finally, treatment-related quality of life (QOL) was not assessed in this study.Because there are no optimal therapeutic sequence criteria for CRPC, symptoms and QOL are important in the choice of treatment as well as anti-tumor efect.Further research is needed to include symptoms, QOL, and other factors.However, these fndings refect daily clinical practice in the real world; thus, our results may be a useful reference.Because patients with CRPC are often older and have comorbidities, not all treatment modalities are available and suitable.Terefore, it should be considered to select treatment individually based on the patient and disease characteristics in situations where appropriate treatment sequence has not been established.

. Conclusion
Tis retrospective study suggests that second-line treatment with ARSI after ARSI as frst-line treatment for CRPC patients is associated with slightly better outcomes compared with DTX in terms of PFS.However, this improvement was not found in the multivariate analysis.Furthermore, our fndings suggest that the ABI-ENZA sequence may have superior anticancer efcacy.Large prospective studies are required to confrm these results and decide the appropriate treatment sequence in CRPC patients.

Figure 1 :
Figure 1: Waterfall plot of the best PSA response rate of each treatment group.(a) ARSI as the frst-line treatment in the ARSI-DTX sequence.(b) ARSI as the frst-line treatment in the ARSI-ARSI sequence.(c) DTX as the second-line treatment in the ARSI-DTX sequence.(d) ARSI as the second-line treatment in the ARSI-ARSI sequence.

Figure 2 :
Figure 2: Kaplan-Meier survival curves for patients with CRPC receiving ARSI and DTX as the second-line treatment.(a) PFS in the second-line treatment.(b) Combined PFS.(c) OS from the frst-line treatment.

Figure 3 :
Figure 3: Kaplan-Meier survival curves for patients with mCRPC receiving ARSI and DTX as the second-line treatment in the subgroup analysis.(a) PFS in the second-line treatment.(b) Combined PFS.(c) OS from the frst-line treatment.

Figure 4 :
Figure 4: Kaplan-Meier survival curves for patients with CRPC by four treatment sequences in the subgroup analysis.(a) Combined PFS.(b) OS from the frst-line treatment.

Table 1 :
Patient characteristics at initiation of frst-and second-line treatment.

Table 2 :
Univariate and multivariate analysis for PFS in second-line treatment.

Table 3 :
Univariate and multivariate analysis for combined PFS.

Table 4 :
Univariate and multivariate analysis for OS.